Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy

J Virol. 2013 Mar;87(5):2508-17. doi: 10.1128/JVI.02319-12. Epub 2012 Dec 19.

Abstract

The mammalian target of rapamycin (mTOR) downstream of phosphatidylinositol 3-kinase (PI3K) in the growth factor receptor (GFR) pathway is a crucial metabolic sensor that integrates growth factor signals in cells. We recently showed that human papillomavirus (HPV) type 16 exposure activates signaling from GFRs in human keratinocytes. Thus, we predicted that the virus would induce the PI3K/mTOR pathway upon interaction with host cells. We detected activation of Akt and mTOR several minutes following exposure of human keratinocytes to HPV type 16 (HPV16) pseudovirions. Activated mTOR induced phosphorylation of the mTOR complex 1 substrates 4E-BP1 and S6K, which led to induction of the functional protein translational machinery. Blockade of epidermal GFR (EGFR) signaling revealed that each of these events is at least partially dependent upon EGFR activation. Importantly, activation of PI3K/Akt/mTOR signaling inhibited autophagy in the early stages of virus-host cell interaction. Biochemical and genetic approaches revealed critical roles for mTOR activation and autophagy suppression in HPV16 early infection events. In summary, the HPV-host cell interaction stimulates the PI3K/Akt/mTOR pathway and inhibits autophagy, and in combination these events benefit virus infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Autophagy*
  • Cell Cycle
  • Cell Line
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Eukaryotic Initiation Factor-4G / metabolism
  • HEK293 Cells
  • Human papillomavirus 16 / physiology*
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / virology
  • PTEN Phosphohydrolase / metabolism
  • Papillomavirus Infections / metabolism
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Virus Internalization*

Substances

  • Adaptor Proteins, Signal Transducing
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factor-4G
  • Phosphoproteins
  • RNA, Messenger
  • RNA, Small Interfering
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • PTEN Phosphohydrolase
  • PTEN protein, human